Prevention and Restriction of Antimicrobial Resistance in Pneumococci by Multi-Level Modelling

Streptococcus pneumoniae is a major health threat in industrialized and developing countries. The pathogen affects both young and old people, immune-competent as well as immunocompromised individuals. By genetic recombination within diverse populations, individual strains are not only able to evade vaccination but also able to acquire antimicrobial resistance (AMR), which can then be transmitted onwards.

This proposal aims to understand the mechanisms and distribution of this pneumococcal AMR repertoire at the genetic, bacterial, host and population levels to layout new strategies for risk assessment, prevention and reduction of AMR. In particular, the environmental, immunological and pharmacological drivers of resistance emergence and selection, the genetic population dynamics, as well as the fitness of the new traits in different host conditions will be analysed and modelled.

To this end, a multinational consortium of researchers with complementary expertise has been formed. Available to the consortium are clinically important and newly emerged pneumococcal AMR strains, together with related patient metadata (clinical, genetic and transcriptomic) from clinical cohorts as well as highly detailed carriage sampling from a Thai cohort. Consortium members have proven expertise in microbiology, bacterial genetics, bioinformatics, in vivo/in vitro models while others are clinicians expert in the treatment of pneumococcal infections in both paediatric and adult patients.

In a concerted effort, this consortium will develop countermeasures against antimicrobial resistance in a major health threat by multi-level modelling of its resistance emergence, selection, and transmission in diverse environments.

The major aim of this consortium is to develop strategies for risk assessment, prevention and reduction of antimicrobial resistance (AMR) by understanding the drivers and mechanisms of AMR development and the consequences on pneumococcal fitness in diverse environments.
We will model of the impact of antibiotic consumption on the pneumococcal evolutionary dynamics of carriage and transmission in the Mae La cohort, to quantify the relative selective effect of different antibiotics. We have identified transmission events and will now begin to explore the diversity within the swabs to obtain a deeper understanding of the amount of variation and change during carriage and transmission. In the Canadian cohorts, we will fully characterise AMR in population-based samples of pneumococcal isolates causing invasive diseases in two distinct Canadian geographic locations, and investigate the molecular determinants in gain and loss of AMR. Total transcriptomes of selected strains and host cells under different experimental conditions will be obtained by RNA-Seq to identify environmental, immunological and pharmacological drivers of AMR emergence.
The specific transmission rates occurring before and after antibiotic treatment will help to decide how to act to limit the prevalence of antibiotic resistance. Some vaccines have had disproportionate effects on drug-resistant lineages within the target species. Our new data may inform our view of whether vaccine introduction, and antibiotics usage promote the spread of resistant bacteria through different mechanisms, including notably the clearing out of susceptible competitors in donors or recipients. This is important in identifying who should be the target of infection control measures, and how these measures should be designed. For instance, if antibiotics make individuals more likely to donate resistant strains to others, they could be treated with combination therapy or higher doses to clear even the resistant bacteria.

Unmet medical need: Streptococcus pneumoniae is a colonizing microbe and a major health threat in industrialized and developing countries, causing pneumonia, sepsis, meningitis and otitis media in young and old people, immune-competent as well as immunocompromised hosts. Thereby, it causes substantial morbidity, mortality and socio-economic costs. It can evade preventive (vaccination) and therapeutic measures (antibiotics) by recombination. Consequently, people remain at risk of severe pneumococcal disease, as vaccination, and conventional antibiotic treatments may fail. Currently, it is unclear how to prevent these harmful developments.
Potential health impact: The project aims to develop new strategies for risk assessment, prevention and reduction of AMR that can be implemented together with relevant health care stakeholders. This may result in new screening policies, altered recommendations for vaccination with higher protection efficiency, and better antibiotic treatment success, with less clinical deterioration and less development of new antibiotic resistance. Finally, morbidity, mortality and socio-economic costs may be reduced.
Exploitation: The project aims to develop and validate real world strategies for risk assessment and prevention of AMR resulting in better vaccination success, improved patient outcomes, less antibiotic consumption and reduced health care costs.
Our improved understanding of the molecular mechanisms will be communicated with the scientific community at conferences and by manuscript publications.
The key stakeholders concerning the health impact are those guiding policy on antimicrobial usage on national and individual patient guidelines. This includes the national and international medical societies (infectious diseases, hygiene, microbiology etc.) and agencies (WHO, CDC, ECDC), the regulatory authorities (e.g. national ministries, STIKO, EMA, FDA), the health insurance systems, health care providers (new SOPs, better trained staff), companies (antimicrobial drugs, vaccination), and last but not least the broader public (health education, patient groups etc.).
Concrete communication activities to promote the project results will be conference lectures for the scientific community. Through the GPS project, we have direct links with collaborators in 45 countries around the world. We also have a strong presence at the major international pneumococcal conferences - ISPPD and Europneumo. With medical societies, regulatory authorities, as well as providers of health insurance or health care, we will organise workshops and consensus meetings resulting in the publications of consensus reports, standard-operating procedures, and probably changes on the terms of drug/vaccination approvals. We will address the public with brochures, publications in newspapers etc. These activities may require initial commitment of the said stakeholders. However, as the main outcome will be improved procedures for antibiotic treatment or vaccination, these measures are expected to save money rather than increase costs. In addition, intellectual property rights will not hamper the exploitation.